Inflammasomes in Cardiovascular Diseases: Current Knowledge and Future Perspectives

Abstract

Chronic inflammation is an important contributor to the development of cardiovascular disorders, and inflammasomes, especially the NOD-like receptor protein 3 (NLRP3), are emerging as crucial mediators in this context. Inflammasomes are activated through receptor-mediated danger signals, such as cholesterol crystals and cellular damage products, thereby stimulating the secretion of pro-inflammatory cytokines, which sustains inflammation. This mechanism drives atherosclerosis (via plaque formation and destabilization), heart failure (via fibrotic remodeling), and pericarditis (via exacerbation of pericardial inflammation). Therapeutic approaches seek to block inflammasome activation or their pro-inflammatory pathways. Colchicine, interleukin-1 inhibitors (anakinra, canakinumab), and Sodium-Glucose Transport Protein 2 (SGLT2) inhibitors have a positive impact on cardiovascular inflammation. Various new compounds, such as MCC950, have been described as novel specific inhibitors of NLRP3. Further studies are needed to validate the effectiveness and safety of these treatments. Further elucidating the role of inflammasomes in cardiovascular disease could open the way to achieving more effective therapies, allowing for better management of high-risk cardiovascular patients.

Keywords: NLRP3; atherosclerosis; cardiovascular diseases; heart failure; inflammasomes; pericarditis.

Figure 1

Priming signals, such as the activation of Toll-like receptors (TLRs) through NF-κB, result in the upregulation of the expression of both NLRP3 and pro-IL-1β. Reactive oxygen species (ROS), thioredoxin-interacting protein (TXNIP) dissociation, and lysosomal rupture are activation signals that trigger the oligomerization of NLRP3. This is conducive to recruiting the signaling adaptor protein ASC and pro-caspase-1, producing the active inflammasome complex. Then, caspase-1 cleaves pro-IL-1β into mature IL-1β and gasdermin D (GSDMD), generating N-terminal GSDMD (N-GSDMD), which forms membrane pores and induces pyroptosis. Tissue inflammation ensues, culminating in the release of inflammatory cytokines and increased recruitment of immune cells. Figure Created in BioRender. Mario Caldarelli. (2025) https://app.biorender.com/illustrations/6834a90177126cc127ecb968?slideId=2778b30d-7e7a-49eb-89c4-5b654ea7eda0 (accessed on 26 May 2025).

Figure 2

The activation of the NLRP3 inflammasome may lead to pathogenic processes in cardiovascular and renal disorders. Though various cellular stressors can cause injury to endothelial cells, impaired function, and thus the activation of thioredoxin-interacting protein (TXNIP), upon activation, the NLRP3 localizes ASC and pro-caspase-1 for the latter to cleave pro-IL-1β into IL-1β and gasdermin D (GSDMD) into its N-terminal form (N-GSDMD). These processes lead to pyroptosis and favor cardiac fibrosis in the onset of cardiovascular and cardiorenal diseases. Figure Created in BioRender. Mario Caldarelli (2025) https://app.biorender.com/illustrations/68349cf16b644c3b97338e6b?slideId=2be5472e-8701-4acd-9302-b3a741c620c5 (accessed on 26 May 2025).